County-level cumulative environmental quality associated with cancer incidence

BACKGROUND

Individual environmental exposures are associated with cancer development; however, environmental exposures occur simultaneously. The Environmental Quality Index (EQI) is a county-level measure of cumulative environmental exposures that occur in 5 domains.

METHODS

The EQI was linked to county-level annual age-adjusted cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) Program state cancer profiles. All-site cancer and the top 3 site-specific cancers for male and female subjects were considered. Incident rate differences (IRDs; annual rate difference per 100,000 persons) and 95% confidence intervals (CIs) were estimated using fixed-slope, random intercept multilevel linear regression models. Associations were assessed with domain-specific indices and analyses were stratified by rural/urban status.

RESULTS

Comparing the highest quintile/poorest environmental quality with the lowest quintile/best environmental quality for overall EQI, all-site county-level cancer incidence rate was positively associated with poor environmental quality overall (IRD, 38.55; 95% CI, 29.57-47.53) and for male (IRD, 32.60; 95% CI, 16.28-48.91) and female (IRD, 30.34; 95% CI, 20.47-40.21) subjects, indicating a potential increase in cancer incidence with decreasing environmental quality. Rural/urban stratified models demonstrated positive associations comparing the highest with the lowest quintiles for all strata, except the thinly populated/rural stratum and in the metropolitan/urbanized stratum. Prostate and breast cancer demonstrated the strongest positive associations with poor environmental quality.

CONCLUSION

We observed strong positive associations between the EQI and all-site cancer incidence rates, and associations differed by rural/urban status and environmental domain. Research focusing on single environmental exposures in cancer development may not address the broader environmental context in which cancers develop, and future research should address cumulative environmental exposures. Cancer 2017. © 2017 American Cancer Society.

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Impact of the environment on cancer: Seeing the forest for the trees

The study by Jagai et al. is a valuable resource for researchers to focus on better understanding associations between environmental quality and cancer incidence, as well as for policy makers to target specific regions and environmental factors within those regions to reduce the burden of cancer in the United States. This study also demonstrates the value of environmental geospatial data, a key tool that provides the empirical scientific evidence base to allow scientists to identify disease-contributing factors and identify vulnerable communities. See also pages 000-000.

from Cancer via ola Kala on Inoreader http://ift.tt/2qfP4Ur
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County-level cumulative environmental quality associated with cancer incidence

BACKGROUND

Individual environmental exposures are associated with cancer development; however, environmental exposures occur simultaneously. The Environmental Quality Index (EQI) is a county-level measure of cumulative environmental exposures that occur in 5 domains.

METHODS

The EQI was linked to county-level annual age-adjusted cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) Program state cancer profiles. All-site cancer and the top 3 site-specific cancers for male and female subjects were considered. Incident rate differences (IRDs; annual rate difference per 100,000 persons) and 95% confidence intervals (CIs) were estimated using fixed-slope, random intercept multilevel linear regression models. Associations were assessed with domain-specific indices and analyses were stratified by rural/urban status.

RESULTS

Comparing the highest quintile/poorest environmental quality with the lowest quintile/best environmental quality for overall EQI, all-site county-level cancer incidence rate was positively associated with poor environmental quality overall (IRD, 38.55; 95% CI, 29.57-47.53) and for male (IRD, 32.60; 95% CI, 16.28-48.91) and female (IRD, 30.34; 95% CI, 20.47-40.21) subjects, indicating a potential increase in cancer incidence with decreasing environmental quality. Rural/urban stratified models demonstrated positive associations comparing the highest with the lowest quintiles for all strata, except the thinly populated/rural stratum and in the metropolitan/urbanized stratum. Prostate and breast cancer demonstrated the strongest positive associations with poor environmental quality.

CONCLUSION

We observed strong positive associations between the EQI and all-site cancer incidence rates, and associations differed by rural/urban status and environmental domain. Research focusing on single environmental exposures in cancer development may not address the broader environmental context in which cancers develop, and future research should address cumulative environmental exposures. Cancer 2017. © 2017 American Cancer Society.

http://ift.tt/2qRvEm0

Impact of the environment on cancer: Seeing the forest for the trees

The study by Jagai et al. is a valuable resource for researchers to focus on better understanding associations between environmental quality and cancer incidence, as well as for policy makers to target specific regions and environmental factors within those regions to reduce the burden of cancer in the United States. This study also demonstrates the value of environmental geospatial data, a key tool that provides the empirical scientific evidence base to allow scientists to identify disease-contributing factors and identify vulnerable communities. See also pages 000-000.

http://ift.tt/2qfP4Ur

Dietary Guidelines for Vitamin D : A vitamin D intake requirement of 14 µg/day would maintain 97.5% of 25(OH)D >50 nmol/L.

http://alexandrossfa.blogspot.com/2017/05/dietary-guidelines-for-vitamin-d.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Endocrine Emergencies : 1. THYROID STORM, 2. MYXEDEMA COMA, 3. DIABETIC KETOACIDOSIS, 4. ACUTE ADRENAL CRISIS

http://alexandrossfa.blogspot.com/2017/05/endocrine-emergencies-1-thyroid-storm-2.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Hypersensitivity pneumonitis (HP) : Dyspnea and cough

http://alexandrossfa.blogspot.com/2017/05/hypersensitivity-pneumonitis-hp-dyspnea.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Association Between the Time to Surgery and Survival Among Patients With Colon Cancer: A Population-Based Study

Publication date: Available online 6 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Jennifer A. Flemming, Sulaiman Nanji, Xuejiao Wei, Colleen Webber, Patti Groome, Christopher M. Booth
Factors associated with time-to-surgery (TTS) and survival in colon cancer has not been well studied. Cancer Care Ontario recommends surgery within 42 days of diagnosis and that 90% of patients meet this benchmark. We describe factors associated with TTS and survival in routine clinical practice. Methods: Retrospective population-based cohort study of patients receiving elective colonic resection after diagnosis of colon cancer in Ontario, Canada from 2002-2008 followed until 2012. Factors associated with TTS were identified using multivariate log-binomial and Quantile regression at 42 days and 90^th percentiles. The association between TTS and cancer-specific (CSS) and overall survival (OS) were examined using multivariate Cox regression. Results: 4,326 patients; median age 71 years and 52% male. Median TTS was 24 days (IQR 14-37); at the 90^th percentile 56 days. Factors associated with TTS ≥ 42 days and > 90^th percentile included older age, co-morbid illness, surgeon volume, and stage I disease (P < 0.05 for all). In patients whose TTS was either at 42 days or 90^th percentile, those ≥ 80 years old waited two weeks longer than those < 60 years, individuals with co-morbid illness waited 10 days longer than without co-morbidity, and patients with stage I disease waited 10 days longer than those with stage IV disease (P < 0.05 for all). Delay in TTS > 42 days or > 90^th percentile was not associated with OS or CSS. Conclusion: Age, co-morbidity, and stage of cancer are associated with TTS. There was no association between TTS and CSS or OS.



http://ift.tt/2poLIdN

Impact of perineural invasion on survival in node negative colon cancer.

Impact of perineural invasion on survival in node negative colon cancer.

Cancer Biol Ther. 2017 May 05;:0

Authors: Mirkin KA, Hollenbeak CS, Mohamed A, Jia Y, El-Deiry WS, Messaris E

Abstract
Perineural invasion (PNI) has been implicated as a poor prognostic indicator in many cancers. The National Comprehensive Cancer Network recommends consideration of observation or adjuvant therapy in the presence of PNI in early colon cancer. These recommendations are based on single institutional studies that fail to evaluate PNI within the context of adjuvant chemotherapy. The US National Cancer Database (2004-2012) was reviewed for patients with node negative colon cancer, and stratified by PNI and receipt of chemotherapy. Of 21,488 patients evaluated, 55.2% had T3 disease (n = 11,852), 23.1% had T2 (n = 4,971), 14.4% had T1 (n = 3,088), and 7.3% had T4 disease (n = 1,577); 4.6% (n = 987) had PNI. Most patients (86.8%, n = 18,641) did not have PNI and did not receive chemotherapy; 8.7% (n = 1,860) did not have PNI but received chemotherapy; 3.7% (n = 785) had PNI and did not receive chemotherapy, and 0.9% (n = 202) had PNI and received chemotherapy. Among those with PNI, patients who received chemotherapy tended to be younger (P<0.001), covered by private insurance (P<0.001), with fewer comorbidities (P<0.001), and greater T stage disease (P<0.001). Those with PNI who received chemotherapy had significantly improved survival over those who did not in T3-4 disease (P<0.001), but not in T1-2 disease. On multivariate analysis, those with PNI had a 38% greater hazard of mortality (HR 1.38, P<0.001). Additionally, chemotherapy decreased the hazard of mortality by 43% (HR 0.57, P<0.001). PNI appears to be an independent poor prognostic indicator in stage T3-4 node negative colon cancer. Chemotherapy administered to this patient population is associated with improved survival.

PMID: 28475454 [PubMed - as supplied by publisher]

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Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Cancer Biol Ther. 2017 May 05;:0

Authors: Starenki D, Hong SK, Wu PK, Park JI

Abstract
Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

PMID: 28475408 [PubMed - as supplied by publisher]

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Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Cancer Biol Ther. 2017 May 05;:0

Authors: Rodgers L, Peer CJ, Figg WD

Abstract
A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.

PMID: 28475407 [PubMed - as supplied by publisher]

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The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Cancer Biol Ther. 2017 May 05;:0

Authors: Kung CP, Liu Q, Murphy ME

Abstract
The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 target CDKN1A (p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the metabolic response genes PPARGC1B (PGC-1β) and PRKAB2 (AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared to P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent.

PMID: 28475405 [PubMed - as supplied by publisher]

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DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

Cancer Biol Ther. 2017 May 05;:0

Authors: De Gregoriis G, Ramos JA, Fernandes PV, Vignal GM, Brianese RC, Carraro DM, Monteiro AN, Struchiner C, Suarez-Kurtz G, Vianna-Jorge R, de Carvalho MA

Abstract
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 Carboxy-Terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of seven tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples. Tumors with worse prognosis (tumor grade 3 and triple negative) showed reduced expression of tBRCT genes, notably, PAXIP1 and TP53BP1. Survival analyses data indicated that tumor status of both genes may impact prognosis. PAXIP1 and 53BP1 protein levels followed gene expression results, i.e., are intrinsically correlated, and also reduced in more advanced tumors. Evaluation of both genes in triple negative breast tumor samples which were characterized for their BRCA1 status showed that PAXIP1 is overexpressed in BRCA1 mutant tumors. Taken together our findings indicate that PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1.

PMID: 28475402 [PubMed - as supplied by publisher]

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Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cancer Biol Ther. 2017 May 05;:0

Authors: Tuerff D, Sissung T, Figg WD

Abstract
A recent publication in Science demonstrates the ability of prostate cancer cells to switch lineages from one that is dependent on androgen signaling to a cell type that is not. Known as lineage plasticity, this phenomenon is driven by the transcription factor SOX2 in RB1 and TP53-deficient prostate cancer. SOX2 is a potential prognostic marker and therapeutic target in castration resistant prostate cancer.

PMID: 28475401 [PubMed - as supplied by publisher]

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Impact of perineural invasion on survival in node negative colon cancer.

Impact of perineural invasion on survival in node negative colon cancer.

Cancer Biol Ther. 2017 May 05;:0

Authors: Mirkin KA, Hollenbeak CS, Mohamed A, Jia Y, El-Deiry WS, Messaris E

Abstract
Perineural invasion (PNI) has been implicated as a poor prognostic indicator in many cancers. The National Comprehensive Cancer Network recommends consideration of observation or adjuvant therapy in the presence of PNI in early colon cancer. These recommendations are based on single institutional studies that fail to evaluate PNI within the context of adjuvant chemotherapy. The US National Cancer Database (2004-2012) was reviewed for patients with node negative colon cancer, and stratified by PNI and receipt of chemotherapy. Of 21,488 patients evaluated, 55.2% had T3 disease (n = 11,852), 23.1% had T2 (n = 4,971), 14.4% had T1 (n = 3,088), and 7.3% had T4 disease (n = 1,577); 4.6% (n = 987) had PNI. Most patients (86.8%, n = 18,641) did not have PNI and did not receive chemotherapy; 8.7% (n = 1,860) did not have PNI but received chemotherapy; 3.7% (n = 785) had PNI and did not receive chemotherapy, and 0.9% (n = 202) had PNI and received chemotherapy. Among those with PNI, patients who received chemotherapy tended to be younger (P<0.001), covered by private insurance (P<0.001), with fewer comorbidities (P<0.001), and greater T stage disease (P<0.001). Those with PNI who received chemotherapy had significantly improved survival over those who did not in T3-4 disease (P<0.001), but not in T1-2 disease. On multivariate analysis, those with PNI had a 38% greater hazard of mortality (HR 1.38, P<0.001). Additionally, chemotherapy decreased the hazard of mortality by 43% (HR 0.57, P<0.001). PNI appears to be an independent poor prognostic indicator in stage T3-4 node negative colon cancer. Chemotherapy administered to this patient population is associated with improved survival.

PMID: 28475454 [PubMed - as supplied by publisher]

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Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Cancer Biol Ther. 2017 May 05;:0

Authors: Starenki D, Hong SK, Wu PK, Park JI

Abstract
Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

PMID: 28475408 [PubMed - as supplied by publisher]

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Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Cancer Biol Ther. 2017 May 05;:0

Authors: Rodgers L, Peer CJ, Figg WD

Abstract
A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.

PMID: 28475407 [PubMed - as supplied by publisher]

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via IFTTT

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Cancer Biol Ther. 2017 May 05;:0

Authors: Kung CP, Liu Q, Murphy ME

Abstract
The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 target CDKN1A (p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the metabolic response genes PPARGC1B (PGC-1β) and PRKAB2 (AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared to P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent.

PMID: 28475405 [PubMed - as supplied by publisher]

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DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

Cancer Biol Ther. 2017 May 05;:0

Authors: De Gregoriis G, Ramos JA, Fernandes PV, Vignal GM, Brianese RC, Carraro DM, Monteiro AN, Struchiner C, Suarez-Kurtz G, Vianna-Jorge R, de Carvalho MA

Abstract
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 Carboxy-Terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of seven tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples. Tumors with worse prognosis (tumor grade 3 and triple negative) showed reduced expression of tBRCT genes, notably, PAXIP1 and TP53BP1. Survival analyses data indicated that tumor status of both genes may impact prognosis. PAXIP1 and 53BP1 protein levels followed gene expression results, i.e., are intrinsically correlated, and also reduced in more advanced tumors. Evaluation of both genes in triple negative breast tumor samples which were characterized for their BRCA1 status showed that PAXIP1 is overexpressed in BRCA1 mutant tumors. Taken together our findings indicate that PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1.

PMID: 28475402 [PubMed - as supplied by publisher]

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via IFTTT

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cancer Biol Ther. 2017 May 05;:0

Authors: Tuerff D, Sissung T, Figg WD

Abstract
A recent publication in Science demonstrates the ability of prostate cancer cells to switch lineages from one that is dependent on androgen signaling to a cell type that is not. Known as lineage plasticity, this phenomenon is driven by the transcription factor SOX2 in RB1 and TP53-deficient prostate cancer. SOX2 is a potential prognostic marker and therapeutic target in castration resistant prostate cancer.

PMID: 28475401 [PubMed - as supplied by publisher]

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via IFTTT

Impact of perineural invasion on survival in node negative colon cancer.

Impact of perineural invasion on survival in node negative colon cancer.

Cancer Biol Ther. 2017 May 05;:0

Authors: Mirkin KA, Hollenbeak CS, Mohamed A, Jia Y, El-Deiry WS, Messaris E

Abstract
Perineural invasion (PNI) has been implicated as a poor prognostic indicator in many cancers. The National Comprehensive Cancer Network recommends consideration of observation or adjuvant therapy in the presence of PNI in early colon cancer. These recommendations are based on single institutional studies that fail to evaluate PNI within the context of adjuvant chemotherapy. The US National Cancer Database (2004-2012) was reviewed for patients with node negative colon cancer, and stratified by PNI and receipt of chemotherapy. Of 21,488 patients evaluated, 55.2% had T3 disease (n = 11,852), 23.1% had T2 (n = 4,971), 14.4% had T1 (n = 3,088), and 7.3% had T4 disease (n = 1,577); 4.6% (n = 987) had PNI. Most patients (86.8%, n = 18,641) did not have PNI and did not receive chemotherapy; 8.7% (n = 1,860) did not have PNI but received chemotherapy; 3.7% (n = 785) had PNI and did not receive chemotherapy, and 0.9% (n = 202) had PNI and received chemotherapy. Among those with PNI, patients who received chemotherapy tended to be younger (P<0.001), covered by private insurance (P<0.001), with fewer comorbidities (P<0.001), and greater T stage disease (P<0.001). Those with PNI who received chemotherapy had significantly improved survival over those who did not in T3-4 disease (P<0.001), but not in T1-2 disease. On multivariate analysis, those with PNI had a 38% greater hazard of mortality (HR 1.38, P<0.001). Additionally, chemotherapy decreased the hazard of mortality by 43% (HR 0.57, P<0.001). PNI appears to be an independent poor prognostic indicator in stage T3-4 node negative colon cancer. Chemotherapy administered to this patient population is associated with improved survival.

PMID: 28475454 [PubMed - as supplied by publisher]

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Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Cancer Biol Ther. 2017 May 05;:0

Authors: Starenki D, Hong SK, Wu PK, Park JI

Abstract
Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

PMID: 28475408 [PubMed - as supplied by publisher]

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via IFTTT

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Cancer Biol Ther. 2017 May 05;:0

Authors: Rodgers L, Peer CJ, Figg WD

Abstract
A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.

PMID: 28475407 [PubMed - as supplied by publisher]

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via IFTTT

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Cancer Biol Ther. 2017 May 05;:0

Authors: Kung CP, Liu Q, Murphy ME

Abstract
The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 target CDKN1A (p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the metabolic response genes PPARGC1B (PGC-1β) and PRKAB2 (AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared to P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent.

PMID: 28475405 [PubMed - as supplied by publisher]

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DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

Cancer Biol Ther. 2017 May 05;:0

Authors: De Gregoriis G, Ramos JA, Fernandes PV, Vignal GM, Brianese RC, Carraro DM, Monteiro AN, Struchiner C, Suarez-Kurtz G, Vianna-Jorge R, de Carvalho MA

Abstract
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 Carboxy-Terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of seven tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples. Tumors with worse prognosis (tumor grade 3 and triple negative) showed reduced expression of tBRCT genes, notably, PAXIP1 and TP53BP1. Survival analyses data indicated that tumor status of both genes may impact prognosis. PAXIP1 and 53BP1 protein levels followed gene expression results, i.e., are intrinsically correlated, and also reduced in more advanced tumors. Evaluation of both genes in triple negative breast tumor samples which were characterized for their BRCA1 status showed that PAXIP1 is overexpressed in BRCA1 mutant tumors. Taken together our findings indicate that PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1.

PMID: 28475402 [PubMed - as supplied by publisher]

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via IFTTT

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cancer Biol Ther. 2017 May 05;:0

Authors: Tuerff D, Sissung T, Figg WD

Abstract
A recent publication in Science demonstrates the ability of prostate cancer cells to switch lineages from one that is dependent on androgen signaling to a cell type that is not. Known as lineage plasticity, this phenomenon is driven by the transcription factor SOX2 in RB1 and TP53-deficient prostate cancer. SOX2 is a potential prognostic marker and therapeutic target in castration resistant prostate cancer.

PMID: 28475401 [PubMed - as supplied by publisher]

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via IFTTT

Impact of perineural invasion on survival in node negative colon cancer.

Impact of perineural invasion on survival in node negative colon cancer.

Cancer Biol Ther. 2017 May 05;:0

Authors: Mirkin KA, Hollenbeak CS, Mohamed A, Jia Y, El-Deiry WS, Messaris E

Abstract
Perineural invasion (PNI) has been implicated as a poor prognostic indicator in many cancers. The National Comprehensive Cancer Network recommends consideration of observation or adjuvant therapy in the presence of PNI in early colon cancer. These recommendations are based on single institutional studies that fail to evaluate PNI within the context of adjuvant chemotherapy. The US National Cancer Database (2004-2012) was reviewed for patients with node negative colon cancer, and stratified by PNI and receipt of chemotherapy. Of 21,488 patients evaluated, 55.2% had T3 disease (n = 11,852), 23.1% had T2 (n = 4,971), 14.4% had T1 (n = 3,088), and 7.3% had T4 disease (n = 1,577); 4.6% (n = 987) had PNI. Most patients (86.8%, n = 18,641) did not have PNI and did not receive chemotherapy; 8.7% (n = 1,860) did not have PNI but received chemotherapy; 3.7% (n = 785) had PNI and did not receive chemotherapy, and 0.9% (n = 202) had PNI and received chemotherapy. Among those with PNI, patients who received chemotherapy tended to be younger (P<0.001), covered by private insurance (P<0.001), with fewer comorbidities (P<0.001), and greater T stage disease (P<0.001). Those with PNI who received chemotherapy had significantly improved survival over those who did not in T3-4 disease (P<0.001), but not in T1-2 disease. On multivariate analysis, those with PNI had a 38% greater hazard of mortality (HR 1.38, P<0.001). Additionally, chemotherapy decreased the hazard of mortality by 43% (HR 0.57, P<0.001). PNI appears to be an independent poor prognostic indicator in stage T3-4 node negative colon cancer. Chemotherapy administered to this patient population is associated with improved survival.

PMID: 28475454 [PubMed - as supplied by publisher]

http://ift.tt/2pQckaa

Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

Cancer Biol Ther. 2017 May 05;:0

Authors: Starenki D, Hong SK, Wu PK, Park JI

Abstract
Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

PMID: 28475408 [PubMed - as supplied by publisher]

http://ift.tt/2po556X

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Diagnosis, Staging, and Risk Stratification in Prostate Cancer: Utilizing Diagnostic Tools to Avoid Unnecessary Therapies and Side Effects.

Cancer Biol Ther. 2017 May 05;:0

Authors: Rodgers L, Peer CJ, Figg WD

Abstract
A lack of appropriate diagnostic tools for prostate cancer has led to overdiagnosis and over treatment. In a recent publication in the New England Journal of Medicine, Hamdy et al showed no difference in the outcomes of patients that had undergone either radical prostatectomy, radiotherapy, or active monitoring. In an effort to enhance clinical stratification, the development of improved, more accurate diagnostic tools is actively being pursued. Herein, we explore recent advances in prostate cancer screening, including biomarker assays, genetic testing, and specialized fields, such as mathematical oncology. These newly developed, highly sensitive diagnostic assays may potentially aid clinicians in selecting appropriate therapies for patients in the very near future.

PMID: 28475407 [PubMed - as supplied by publisher]

http://ift.tt/2pnzjXK

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

The codon 72 polymorphism of p53 influences cell fate following nutrient deprivation.

Cancer Biol Ther. 2017 May 05;:0

Authors: Kung CP, Liu Q, Murphy ME

Abstract
The TP53 gene is distinguished as the most frequently mutated gene in cancer. Unlike most cancer-relevant genes, the TP53 gene is also distinguished by the existence of coding region polymorphisms that alter p53 sequence, and in some cases, also alter p53 function. A common coding region variant at amino acid 72 of p53 encodes either proline (P72) or arginine (R72). P72 is the ancestral variant and is most common in populations near the equator. The frequency of the R72 variant increases in a linear manner with latitude. To date, why the R72 variant arose in humans and was possibly selected for has remained unclear. Here-in we show that this single nucleotide polymorphism (SNP) influences the phosphorylation of p53 and the transactivation of the key p53 target CDKN1A (p21) specifically in response to nutrient deprivation, but not in response to conventional cytotoxic agents. Following activation of the kinase AMPK, R72 cells show increased phosphorylation on serine-15 and increased transactivation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the metabolic response genes PPARGC1B (PGC-1β) and PRKAB2 (AMPK-β2). This is accompanied by increased growth arrest and decreased apoptosis in R72 cells compared to P72 cells. The combined data fit best with the hypothesis that the R72 polymorphism confers increased cell survival in response to nutrient deprivation. This differential response to nutrient deprivation may explain part of selection for this SNP at northern latitudes, where nutrient deprivation might have been more frequent.

PMID: 28475405 [PubMed - as supplied by publisher]

http://ift.tt/2pQkE9Z

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.

Cancer Biol Ther. 2017 May 05;:0

Authors: De Gregoriis G, Ramos JA, Fernandes PV, Vignal GM, Brianese RC, Carraro DM, Monteiro AN, Struchiner C, Suarez-Kurtz G, Vianna-Jorge R, de Carvalho MA

Abstract
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 Carboxy-Terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of seven tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples. Tumors with worse prognosis (tumor grade 3 and triple negative) showed reduced expression of tBRCT genes, notably, PAXIP1 and TP53BP1. Survival analyses data indicated that tumor status of both genes may impact prognosis. PAXIP1 and 53BP1 protein levels followed gene expression results, i.e., are intrinsically correlated, and also reduced in more advanced tumors. Evaluation of both genes in triple negative breast tumor samples which were characterized for their BRCA1 status showed that PAXIP1 is overexpressed in BRCA1 mutant tumors. Taken together our findings indicate that PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1.

PMID: 28475402 [PubMed - as supplied by publisher]

http://ift.tt/2pnZttd

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cellular identity crisis: antiandrogen resistance by lineage plasticity.

Cancer Biol Ther. 2017 May 05;:0

Authors: Tuerff D, Sissung T, Figg WD

Abstract
A recent publication in Science demonstrates the ability of prostate cancer cells to switch lineages from one that is dependent on androgen signaling to a cell type that is not. Known as lineage plasticity, this phenomenon is driven by the transcription factor SOX2 in RB1 and TP53-deficient prostate cancer. SOX2 is a potential prognostic marker and therapeutic target in castration resistant prostate cancer.

PMID: 28475401 [PubMed - as supplied by publisher]

http://ift.tt/2pQdXEM

Clinicopathological and Molecular Study of Triple-Negative Breast Cancer in Algerian Patients

Abstract

Triple-negative breast cancer (TNBC) is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. There are limited data regarding TNBC among Algerian women. In this study, we sought to determine clinical and tumor characteristics associated with TNBC. We also screened for the prevalence of BRCA1 mutations in unselected cohort of TNBC patients. Clinical and tumor characteristics data of 877 breast cancer patients diagnosed between 2011 and 2015, were collected from cancer registry of public hospital of Rouiba. Patients were divided in two groups: those with TNBC and those with other breast cancer subtypes. Differences between the two groups with regard to clinical and tumor characteristics were compared using Fisher's exact test. BRCA1 mutations analysis was performed in unselected cohort of 103 women with TNBC, including all exons where a mutation was previously found in Algerian population (exons 2, 3, 5, 11). The median age at diagnosis for TNBC and non-TNBC patients was 47.4 years and 49.4 years, respectively. The proportion of TNBC was 19.95%. Our data showed significant differences in menopausal status, TNM stage, histological type, tumor histological grade, Ki67 expression and family history of breast cancer between TNBC and non-TNBC patients. Four distinct deleterious mutations in BRCA1 gene were detected in eight young TNBC patients. TNBC is associated with young age, poor histopathological characteristics and family history of breast cancer. BRCA1 mutations have been detected in young TNBC patients. TNBC phenotype should be added as criterion to screen for BRCA1 mutations in Algerian women.

from Cancer via ola Kala on Inoreader http://ift.tt/2qbGHcq
via IFTTT

Clinicopathological and Molecular Study of Triple-Negative Breast Cancer in Algerian Patients

Abstract

Triple-negative breast cancer (TNBC) is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. There are limited data regarding TNBC among Algerian women. In this study, we sought to determine clinical and tumor characteristics associated with TNBC. We also screened for the prevalence of BRCA1 mutations in unselected cohort of TNBC patients. Clinical and tumor characteristics data of 877 breast cancer patients diagnosed between 2011 and 2015, were collected from cancer registry of public hospital of Rouiba. Patients were divided in two groups: those with TNBC and those with other breast cancer subtypes. Differences between the two groups with regard to clinical and tumor characteristics were compared using Fisher's exact test. BRCA1 mutations analysis was performed in unselected cohort of 103 women with TNBC, including all exons where a mutation was previously found in Algerian population (exons 2, 3, 5, 11). The median age at diagnosis for TNBC and non-TNBC patients was 47.4 years and 49.4 years, respectively. The proportion of TNBC was 19.95%. Our data showed significant differences in menopausal status, TNM stage, histological type, tumor histological grade, Ki67 expression and family history of breast cancer between TNBC and non-TNBC patients. Four distinct deleterious mutations in BRCA1 gene were detected in eight young TNBC patients. TNBC is associated with young age, poor histopathological characteristics and family history of breast cancer. BRCA1 mutations have been detected in young TNBC patients. TNBC phenotype should be added as criterion to screen for BRCA1 mutations in Algerian women.

http://ift.tt/2qbGHcq